Gaia Spadarella

Old and new oral anticoagulants: Food, herbal medicines and drug interactions

The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter medications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications.

Ensuring medication adherence with direct oral anticoagulant drugs Lessons from adherence with vitamin K antagonists (VKAs)

Medication adherence (taking drugs properly) is uncommon among patients on warfarin. Poor adherence to warfarin leads to an increase in adverse medical events, including stroke in atrial fibrillation (AF). Factors related to patients, physicians and the health system account for poor adherence. Direct oral anticoagulants (DOACs) are easier to use than warfarin, with fewer drug and food interactions and no need for routine blood monitoring. A proper use of DOACs may reduce the risk of stroke in AF. However, in clinical settings where no laboratory monitoring is needed, a poor medication adherence is common and may impact clinical outcomes. In the management of chronic disorders, careful knowledge of the individual patients attitudes and behaviors is a pre-requisite for a successful doctor-patient communication. To increase patients awareness of the risks and benefits of DOACs and, in turn, increase medication adherence, at each follow-up visit physicians should screen for priorities and motivational problems; check for the lack of understanding and/or knowledge; assess any health system or personal barriers to medication adherence; identify appropriate interventions and provide tailored support to patient needs. Dissemination of guidelines to the health care chain (prescribing physician, general practitioners, caregivers, nurses, pharmacists) further encourages medication adherence. However, the long-term effect of some of these strategies is unknown; one tool may not fit all patients, and the prescribing physician should consider individualization of these aids to ensure medication adherence and persistence (continuing to take drugs properly in long-term treatments) for DOACs in every day practice.

Antithrombotic drugs, patient characteristics, and gastrointestinal bleeding: Clinical translation and areas of research

Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. Current understanding of the roles of platelet activation and thrombin generation/activity in vascular medicine has led to the development of effective antithrombotic treatments. However, in parallel with a sustained coronary and cerebral flow patency, the increasingly intensive treatment with warfarin; direct oral anticoagulant drugs [DOACs], and/or with aspirin ± clopidogrel (or ± prasugrel or ± ticagrelor), has increased the burden of GIBs related to the use of antithrombotic agents. Compelling evidence concerning this issue is accumulating to indicate that: 1) the risk of GIB related to the use of antithrombotic drugs dramatically differs in different clinical settings; and 2) the characteristics of patients (e.g., severity of illness, comorbidities) in whom it is used exert a greater impact on the risk of GIB than the type of antithrombotic agent employed. The latter concept argues for the occurrence of GIB as reflecting the presence of patients at the highest risk for adverse outcomes. The HAS-BLED score identifies subjects at risk of bleeding among those untreated and those treated with warfarin, DOACs and/or low-dose aspirin. Its use within the frame of a severity score (e.g., the CHA2DS2-VASc score in patients with atrial fibrillation) helps balance the benefits and the risks of an antithrombotic treatment and identify those patients in whom the absolute gain (vascular events prevented) outweighs the risk of GIB. Potential implications of the latter information in settings other than atrial fibrillation is thoroughly discussed.

The risk of coronary artery disease and cerebrovascular disease in patients with hepatitis C: A systematic review and meta-analysis

BACKGROUND/OBJECTIVES Some studies suggest that patients with hepatitis C virus (HCV) infection have an increased risk of coronary artery disease (CAD) and cerebrovascular disease. Unfortunately, available data on this association are widely variable. We have performed a systematic review and meta-analysis of literature to evaluate the risk of cardio-cerebrovascular disease (CCD) associated with HCV. METHODS Studies reporting on CCD risk associated with HCV were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS Twenty-seven studies (34 data-sets) showed a significantly increased CCD risk in 297,613 HCV patients as compared with 557,814 uninfected controls (OR: 1.428; 95% CI: 1.214, 1.681). These results were confirmed when separately considering the risk of CAD (20 studies, OR: 1.382; 95% CI: 1.103, 1.732) and of cerebrovascular disease (13 studies, OR: 1.485; 95% CI: 1.079, 2.044). Similar results were confirmed when analyzing 21 studies reporting adjusted risk estimates (OR: 1.448; 95% CI: 1.218, 1.722) and when, after excluding studies defining CAD as positive angiographic or electrocardiographic evidence, we specifically included the 17 studies reporting on acute CCD-related events (OR: 1.357; 95% CI: 1.103, 1.670). Moreover, 4 studies evaluating CCD-related deaths showed a higher risk in HCV patients than controls (OR: 1.772; 95% CI: 1.448, 2.168; P<0.0001). Meta-regression models suggested a direct association between prevalence of cirrhosis and difference in CCD risk between HCV patients and controls. CONCLUSIONS Results of our large meta-analysis suggest that HCV-infected subjects experience an increased risk of CCD. This should be considered to plan specific cardiovascular prevention strategies in this clinical setting.

The risk of osteoporosis in patients with liver cirrhosis: a meta-analysis of literature studies

Data about the association between cirrhosis and osteoporosis are contrasting. Thus, we have performed a meta‐analysis of literature studies on this topic.

Clinical judgment when using coagulation tests during direct oral anticoagulant treatment: A concise review

Because their anticoagulant effect is dose predictable, steady, and little influenced by diet and drugs, laboratory monitoring was deemed unnecessary in trials on venous and arterial thromboprophylaxis with the direct oral anticoagulant drugs (DOACs) rivaroxaban, apixaban, edoxaban, or dabigatran. However, there are special clinical settings in which measurement of their anticoagulant effect may be clinically desired. Because of lack of standardization between reagents employed and their global nature, the activated partial thromboplastin time (APTT) and the prothrombin time (PT) are not generally suitable for accurately assessing the anticoagulant effect of DOACs. The modified (diluted) PT reliably quantifies the anticoagulant effect of rivaroxaban or of apixaban. However, a higher intraindividual variability from one PT reagent to another is found when the data are compared with those obtained with standard PT. The HEMOCLOT (HYPHEN BioMed, France) assay is a modified (diluted) thrombin time (TT) provided with dabigatran calibrators. However, it is performed only in few specialized centers. Anti-factor Xa (anti-FXa) chromogenic assays employ routine automated coagulometers or manual spectrometers, and kits for anti-FIIa assays that measure dabigatran levels and kits for anti-Xa with rivaroxaban calibrators are commercially available. However, no correlation has been identified between any of these tests and clinical outcomes in patients taking any of the DOACs. Thus, currently, there are evidence gaps regarding the role of laboratory testing for surveillance and management of adverse events associated with DOACs. In view of this, in addition to standardization, validation of such assays is mandatory before they can be used to make clinical decisions.

Gastrointestinal bleeding in patients receiving oral anticoagulation: Current treatment and pharmacological perspectives

Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. The rate of major GIB related to the use of some direct acting oral anticoagulant drugs (DOACs), is higher than that detected in warfarin users. Current strategies in the treatment of GIBs in patients receiving warfarin or DOACs (vitamin K, activated charcoal; hemodialysis; recombinant factor VIIa; [activated] prothrombin complex concentrates) including indications for the treatment of bleeding based on different degrees of severity of the episodes, is reported in this article. Potential preventive strategies to mitigate the risk of GIBs (e.g. upper endoscopy/biopsy, colon cancer screening; eradication of Helicobacter pylori prior to starting anticoagulation; use of proton-pump inhibitors, identification of risk factors for bleeding) are also reported as well as the fact that some of them have not been tested so far in patients receiving DOACs. Antidotes that experimentally reverse the anti-coagulant effect of dabigatran (Idarucizumab; BI 655075; Boehringer Ingelheim); of rivaroxaban, apixaban, or edoxaban (Andexanet alfa, r-Antidote, PRT064445; Portola Pharmaceuticals) or of all DOACs (Aripazine, PER-977, ciraparantag; Perosphere Inc.) are discussed. Likewise, population pharmacokinetics modeling related to the rate of major DOACs-related GIBs is presented. It is also emphasized that the occurrence of GIB reflects the presence of patients at the highest risk for adverse outcomes. Finally, the implications of the concept that patient characteristics and the severity of illness (i.e. comorbidities) exert a greater impact on the risk of GIB than the type of antithrombotic agent employed, are analyzed.

Systematic reviews and meta-analyses for more profitable strategies in peripheral artery disease.

Abstract In the peripheral arteries, a thrombus superimposed on atherosclerosis contributes to the progression of peripheral artery disease (PAD), producing intermittent claudication (IC), ischemic necrosis, and, potentially, loss of the limb. PAD with IC is often undiagnosed and, in turn, undertreated. The low percentage of diagnosis (∼30%) in this setting of PAD is of particular concern because of the potential worsening of PAD (amputation) and the high risk of adverse vascular outcomes (vascular death, coronary artery disease, stroke). A Medline literature search of the highest-quality systematic reviews and meta-analyses of randomized controlled trials documents that, due to risk of bias, imprecision, and indirectness, the overall quality of the evidence concerning diagnostic tools and antithrombotic interventions in PAD is generally low. Areas of research emerge from the information collected. Appropriate treatments for PAD patients will only derive from ad-hoc studies. Innovative imaging techniques are needed to identify PAD subjects at the highest vascular risk. Whether IC unresponsive to physical exercise and smoking cessation identifies those with a heritable predisposition to more severe vascular events deserves to be addressed. Devising ways to improve prevention of vascular events in patients with PAD implies a co-ordinated approach in vascular medicine.

Methylation Reactions, the Redox Balance and Atherothrombosis: The Search for a Link with Hydrogen Sulfide

It is now clear that homocysteine (Hcy) is irreversibly degraded to hydrogen sulfide (H(2)S), an endogenous gasotransmitter that causes in vivo platelet activation via upregulation of phospholipase A2 and downstream boost of the arachidonate cascade. This mechanism involves a transsulfuration pathway. Based on these new data, clinical and experimental models on the relationships between Hcy and folate pathways in vascular disease and information on the Hcy controversy have been reanalyzed in the present review. Most interventional trials focused on Hcy lowering by folate administration did not exclude patients routinely taking the arachidonate inhibitor aspirin. This may have influenced the results of some of these trials. It is also clear that nutritional intake of folate affects several enzymatic reactions of the methionine-Hcy cycle and associated one-carbon metabolism and, thereby, both methylation reactions and redox balance. Hence, it is conceivable that the abnormally high Hcy levels seen in pathologic states reflect a poorly elucidated perturbation of such reactions and of such balance. While it is unknown whether there is an interplay between H2S, methylation reactions, and redox balance, measuring the sole reduction of blood Hcy that follows folate administration may well be an oversimplified approach to a complex biologic perturbation. The need to investigate this complex framework is thoroughly discussed in this article.

Attempting to remedy sub-optimal medication adherence in haemophilia: The rationale for repeated ultrasound visualisations of the patient's joint status

Haemophilia is marked by joint bleeding (haemarthrosis) leading to cartilage damage (arthropathy). Lifelong prophylaxis-initiated after the first bleeding episode-leads to a dramatic decrease in arthropathy in haemophilia patients. However, adherence to continuous intravenous administrations of factor VIII (FVIII) or FIX products is challenging, and patients potentially suffer from breakthrough bleedings while on prophylaxis. Newer FVIII/FIX products with enhanced convenience attributes and/or easier infusion procedures are intended to improve adherence. However, pharmacokinetic data should be harmonised with information from individual attitudes and treatment needs, to tailor intravenous dosing and scheduling in patients who receive extended half-life products. Nor is there sound evidence as to how subcutaneous non-FVIII/FIX replacement approaches (concizumab; emicizumab; fitusiran) or single intravenous injections of adeno-associated viral vectors (when employing gene therapy) will revolutionize adherence in haemophilia. In rheumatoid arthritis, repeated ultrasound examination of a patients major joints is a valuable tool to educate patients and parents to understand the disease and provide an objective framework for clinicians to acknowledge patients adherence. Joint ultrasound examination in haemophilia significantly correlates with cartilage damage, effusion, and synovial hypertrophy evaluated by magnetic resonance imaging. Furthermore, in patients with haemophilia undergoing prophylaxis with an extended half-life product for a ≈ 2.8 year period, a significant continued improvement in joint health is detected at the physical examination. This provides the rationale for studies on repeated ultrasound examinations of joint status to attempt to remedy sub-optimal medication adherence and help identify which approach is most suited on which occasion and for which patient.